Estrogen therapy improves endothelium-dependent vasodilation by enhancing nitric oxide (NO) bioactivity, which has atheroprotective implications, but is not acceptable for chronic use by many women. L- arginine may improve endothelium-dependent vasodilation by providing additional substrate for NO synthesis and thus be an acceptable substitute. We measured serum nitrogen oxides (Griess reagent technique) on a nitrate-restricted diet (as an index of endothelial NO release), brachial artery flow-mediated dilation by ultrasound following forearm ischemia (as an index of endothelial NO bioactivity), and soluble cell adhesion molecules (as an index of NO-regulated inflammatory markers) in 10 postmenopausal women at least 2 months off hormone therapies. Subjects were randomly assigned to L-arginine 9 gm or placebo daily for 1 month, with crossover to the alternate treatment after 1 month off-therapy in a double-blind study. Compared with placebo, L-arginine therapy increased serum levels of L-arginine (mean+/-SD: 136+/-63 vs. 75+/-16 +/-mol/L, P=0.009). However, there were no significant differences in serum nitrogen oxides (42.1+/-24.5 vs. 39.1+/-16.6 micromol/L, P=0.61), flow-mediated dilation (3.8+/-3.0 vs. 4.9+/-4.8%, P=0.53), or serum levels of E-selectin (50.6+/-14.8 vs. 52.1+/-17.0 ng/mL, P=0.45), intercellular adhesion molecule-1 (230+/-51 vs. 230+/-52 ng/mL, P=0.97), and vascular cell adhesion molecule-1 (456+/-62 vs. 469+/-91 ng/mL, P=0.53). We conclude that oral L-arginine therapy may not augment endothelial NO release or bioactivity in postmenopausal women and accordingly, is unlikely to be of atheroprotective benefit to healthy postmenopausal women. - L-Arginine, endothelium-dependent, estrogen, nitric oxide - Human Subjects